Anti-Amyloid β monoclonal antibody, clone 83F2

Following traumatic brain injury (TBI) neurological damage is ongoing through a complex cascade of primary and secondary injury events in the ensuing minutes, days and weeks. The delayed nature of secondary injury provides a valuable window of opportunity to limit the consequences with a timely treatment. Recently, the amyloid precursor protein (APP) and its derivative APP96-110 have shown encouraging neuroprotective activity following TBI following an intracerebroventricular administration. Nevertheless, its broader clinical utility would be enhanced by an intravenous (IV) administration. This study assessed the efficacy of IV APP96-110, where a dose-response for a single dose of 0.005mg/kg +/- 0.5mg/ kg APP96-110 at either 30 minutes or 5 hours following moderate-severe diffuse impactacceleration injury was performed. Male Sprague-Dawley rats were assessed daily for 3 or 7 days on the rotarod to examine motor outcome, with a separate cohort of animals utilised for immunohistochemistry analysis 3 days post-TBI to assess axonal injury and neuroinflammation. Animals treated with 0.05mg/kg or 0.5mg/kg APP96-110 after 30 minutes demonstrated significant improvements in motor outcome. This was accompanied by a reduction in axonal injury and neuroinflammation in the corpus callosum at 3 days post-TBI, whereas 0.005mg/kg had no effect. In contrast, treatment with 0.005m/kg or 0.5mg/kg APP96-110 at 5 hours post-TBI demonstrated significant improvements in motor outcome over 3 days, which was accompanied by a reduction in axonal injury in the corpus callosum. This demonstrates that APP96-110 remains efficacious for up to 5 hours post-TBI when administered IV, and supports its development as a novel therapeutic compound following TBI.

Conventional Type Ia supernova (SN Ia) cosmology analyses currently use a simplistic linear regression of magnitude versus color and light curve shape, which does not model intrinsic SN Ia variations and host galaxy dust as physically distinct effects, resulting in low color-magnitude slopes. We construct a probabilistic generative model for the dusty distribution of extinguished absolute magnitudes and apparent colors as the convolution of an intrinsic SN Ia color-magnitude distribution and a host galaxy dust reddening-extinction distribution. If the intrinsic color-magnitude (M-B versus B-V) slope beta(int) differs from the host galaxy dust law R-B, this convolution results in a specific curve of mean extinguished absolute magnitude versus apparent color. The derivative of this curve smoothly transitions from beta(int) in the blue tail to R-B in the red tail of the apparent color distribution. The conventional linear fit approximates this effective curve near the average apparent color, resulting in an apparent slope beta(app) between beta(int) and R-B. We incorporate these effects into a hierarchical Bayesian statistical model for SN Ia light curve measurements, and analyze a data set of SALT2 optical light curve fits of 248 nearby SNe Ia at z < 0.10. The conventional linear fit gives beta(app) approximate to 3. Our model finds beta(int) = 2.3 +/- 0.3 and a distinct dust law of R-B = 3.8 +/- 0.3, consistent with the average for Milky Way dust, while correcting a systematic distance bias of similar to 0.10 mag in the tails of the apparent color distribution. Finally, we extend our model to examine the SN Ia luminosity-host mass dependence in terms of intrinsic and dust components.